Amyotrophic lateral sclerosis (ALS);
Lou Gehrig's disease

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons. The hallmark of this disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Mutant superoxide dismutase 1 (SOD1), as seen in some familial ALS (FALS) cases, is unstable, forming aggregates in the motor neuron cytoplasm, axoplasm and mitochondria. Within mitochondria, mutant SOD1 may interfere with the anti-apoptotic function of Bcl-2, affect mitochondrial import by interfering with the translocation machinery (TOM/TIM), and generate toxic free radicals (ROS). Reactive oxygen species (ROS), produced within mitochondria, inhibit the function of EAAT2, the main glial glutamate transporter protein, responsible for most of the reuptake of synaptically released glutamate. Glutamate excess increases intracellular calcium, which enhances oxidative stress and mitochondrial damage. Mutant SOD1 can also trigger oxidative reactions , which can then cause damage through the formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. Nitration may target neurofilament proteins, affecting axonal transport. Collectively, these mechanisms are predicted to disturb cellular homeostasis, ultimately triggering motor neuron death.

Neurodegenerative disease

(ALS1) SOD1; superoxide dismutase (mutation) [HSA:6647] [KO:K04565]
(ALS2) ALS2; alsin (mutation) [HSA:57679] [KO:K04575]
(ALS4) SETX; senataxin (mutation) [HSA:23064] [KO:K10706]
(ALS6) FUS; fusion (mutation) [HSA:2521] [KO:K13098]
(ALS8) VAPB; VAMP-associated protein (mutation) [HSA:9217] [KO:K10707]
(ALS9) ANG; angiogenin (mutation) [HSA:283] [KO:K16631]
(ALS10) TARDBP; TAR DNA binding protein (mutation) [HSA:23435]
(ALS11) FIG4; FIG4 homolog (mutation) [HSA:9896]
(ALS12) OPTN; optineurin (mutation) [HSA:10133]
NEFH; neurofilament, heavy polypeptide (deletion/insertion in KSP repeat motif) [HSA:4744] [KO:K04574]
PRPH; peripherin (deletion) [HSA:5630] [KO:K07607]
DCTN1; dynactin 1 (mutation) [HSA:1639] [KO:K04648]
MAPT; microtubule-associated protein tau [HSA:4137] [KO:K04380]

Riluzole [DR:D00775] glutamate release inhibitor

Affected region: motor cortex, brain stem, spinal cord
Microscopic lesion: hyaline inclusions

PMID:19251628 (ALS6)

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE

Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.

Science 323:1208-11 (2009)

PMID:19251627 (ALS6)

Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr

Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.

Science 323:1205-8 (2009)

PMID:19118816 (ALS11)

Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, Figlewicz D, Brown RH, Meisler MH

Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.

Am J Hum Genet 84:85-8 (2009)

PMID:19081518 (drug)

Turner MR, Kiernan MC, Leigh PN, Talbot K

Biomarkers in amyotrophic lateral sclerosis.

Lancet Neurol 8:94-109 (2009)

PMID:18802454 (ALS10)

Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L, Rademakers R

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral  sclerosis.

PLoS Genet 4:e1000193 (2008)

PMID:16924260

Pasinelli P, Brown RH

Molecular biology of amyotrophic lateral sclerosis: insights from genetics.

Nat Rev Neurosci 7:710-23 (2006)

PMID:16503123

Gros-Louis F, Gaspar C, Rouleau GA

Genetics of familial and sporadic amyotrophic lateral sclerosis.

Biochim Biophys Acta 1762:956-72 (2006)

PMID:16501576 (ALS9)

Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH Jr, Hardiman O

ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis.

Nat Genet 38:411-3 (2006)

PMID:15952898 (ALS1)

Valentine JS, Doucette PA, Zittin Potter S

Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.

Annu Rev Biochem 74:563-93 (2005)

PMID:15478096 (ALS4)

Kunst CB

Complex genetics of amyotrophic lateral sclerosis.

Am J Hum Genet 75:933-47 (2004)

PMID:15106121

Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF

DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).

Am J Hum Genet 74:1128-35 (2004)

PMID:11239414

Julien JP.

Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.

Cell 104:581-91 (2001)

PMID:20428114 (ALS12)

Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H

Mutations of optineurin in amyotrophic lateral sclerosis.

Nature 465:223-6 (2010)